NATIONAL ACADEMY PRESS
2101 Constitution Avenue, NW Washington, DC 20418
NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, National Academy of Engineering, and Institute of Medicine. The members of the committee responsible for the report were chosen for their special competencies and with regard for appropriate balance.
This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, National Academy of Engineering, and Institute of Medicine.
This project was supported by the National Center for Research Resources, National Institutes of Health (Grant R24 RR04523-02); American Veterinary Medical Association; Animal and Plant Health Inspection Service, U.S. Department of Agriculture (Grants 12-34-93-0090-IA and 12-34-61-001-GR); Center for Veterinary Medicine, Food and Drug Administration and Animal Welfare Information Service, National Agricultural Library, U.S. Department of Agriculture (Combined Grant 59-32U4-7-125); Association of American Veterinary Medical Colleges; Charles River Laboratories, Inc.; and E. I. du Pont de Nemours & Company. The views, opinions, and findings contained in this report are those of the committee and should not be construed as an official position, policy, or decision of the sponsoring organizations unless so designated by other documentation.
Library of Congress Cataloging-in-Publication Data
Recognition and alleviation of pain and distress in laboratory animals /Committee on Pain and Distress in Laboratory Animal, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council.
p. cm.
Includes bibliographical references and index.
ISBN 0-309-04275-5
1. Laboratory animals—Diseases. 2. Pain in animals. 3. Laboratory animals—Effect of stress on. 4. Animal welfare. I. Institute of Laboratory Animal Resources (U.S.). Committee on Pain and Distress in Laboratory Animals.
[DNLM: 1. Animals, Laboratory. 2. Animal Welfare. 3. Pain— prevention & control 4. Stress—veterinary. QY 54 R311]
SF996.5R43 1992
636.088´5—dc20
DNLM/DLC
for Library of Congress 92-8266
CIP
Copyright © 1992 by the National Academy of Sciences
Printed in the United States of America
First Printing, June 1992
Second Printing, January 1993
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The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice-chairman, respectively, of the National Research Council.
COMMITTEE ON PAIN AND DISTRESS IN LABORATORY ANIMALS
Arthur L. Aronson (Chairman),
North Carolina State University, Raleigh, North Carolina
J. Derrell Clark,
University of Georgia, Athens, Georgia
Ronald Dubner,
National Institutes of Health, Bethesda, Maryland
G. F. Gebhart,
University of Iowa, Iowa City, Iowa
Howard C. Hughes, JR.,
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania
William A. Mason,
University of California, Davis, California
J. Anthony Movshon,
New York University, New York, New York
Andrew N. Rowan,
Tufts University, North Grafton, Massachusetts
Jeri A. Sechzer,
Cornell University Medical College, New York, New York
Lawrence R. Soma,
University of Pennsylvania, Kennett Square, Pennsylvania
Staff
Thomas L. Wolfle, Director,
Institute of Laboratory Animal Resources
Dorothy D. Greenhouse, Senior Program Officer
Mara L. Aimone, Senior Staff Assistant
Amanda E. Huli, Senior Staff Assistant
Roberta J. Kahlow, Administrative Secretary (Budget)
Carol M. Rozmiarek, Secretary
Norman Grossblatt, Editor
INSTITUTE OF LABORATORY ANIMAL RESOURCES COUNCIL
Steven P. Pakes (Chairman),
University of Texas Southwestern Medical Center, Dallas, Texas
June R. Aprille,
Tufts University, Boston, Massachusetts
Melvin W. Balk,
Charles River Laboratories, Inc., Wilmington, Massachusetts
J. Derrell CLARK,
University of Georgia, Athens, Georgia
Lester M. Crawford,
National Food Processors Association, Washington, D.C.
Neal First,
University of Wisconsin, Madison, Wisconsin
Thomas J. Gill III,
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Alan M. Goldberg,
Johns Hopkins University, Baltimore, Maryland
Jon W. Gordon,
Mt. Sinai School of Medicine, New York, New York
John P. Hearn,
Wisconsin Regional Primate Research Center, Madison, Wisconsin
Margaret Z. Jones,
Michigan State University, East Lansing, Michigan
Michael D. Kastello,
Merck Sharp & Dohme, Rahway, New Jersey
J. Wesley Robb,
University of Southern California, Los Angeles, California
John L. Vandeberg,
Southwest Foundation for Biomedical Research, San Antonio, Texas
Thomas L. Wolfle, Director,
Institute of Laboratory Animal Resources
The Institute of Laboratory Animal Resources (ILAR) was founded in 1952 under the auspices of the National Research Council. Its mission is to provide expert counsel on the scientific, technologic, and ethical use of laboratory animals within the context of the interests and the mission of the National Academy of Sciences, which is to promote the application of science for the public welfare. ILAR promotes the high-quality and humane care of laboratory animals, the appropriate use of laboratory animals, and the exploration of alternatives in research, testing, and teaching. ILAR serves as an advisory group to the federal government, the biomedical research community, and the public.
COMMISSION ON LIFE SCIENCES
Bruce M. Alberts (Chairman),
University of California, San Francisco, California
Bruce N. Ames,
University of California, Berkeley, California
J. Michael Bishop,
University of California Medical Center, San Francisco, California
Michael T. Clegg,
University of California, Riverside, California
Glenn A. Crosby,
Washington State University, Pullman, Washington
Leroy E. Hood,
California Institute of Technology, Pasadena, California
Donald F. Hornig,
Harvard School of Public Health, Boston, Massachusetts
Marian E. Koshland,
University of California, Berkeley, California
Richard E. Lenski,
Michigan State University, East Lansing, Michigan
Steven P. Pakes,
University of Texas Southwestern Medical Center, Dallas, Texas
Emil A. Pfitzer,
Hoffmann-LaRoche Inc., Nutley, New Jersey
Thomas D. Pollard,
Johns Hopkins University Medical School, Baltimore, Maryland
Joseph E. Rall,
National Institutes of Health, Bethesda, Maryland
Richard D. Remington,
University of Iowa, Iowa City, Iowa
Paul G. Risser,
University of New Mexico, Albuquerque, New Mexico
Harold M. Schmeck, JR.,
Armonk, New York
Richard B. Setlow,
Brookhaven National Laboratory, Upton, New York
Carla J. Shatz,
University of California, Berkeley, California
Torsten N. Wiesel,
Rockefeller University, New York, New York
John E. Burris, Executive Director,
Commission on Life Sciences
Preface
Animals contribute in important ways to the advancement of biology and to the understanding, prevention, and treatment of diseases of humans and other animals. Beginning with the work of Jenner, Pasteur, and Koch in animals over 200 years ago, vaccines have controlled or eliminated human scourges of smallpox, rabies, yellow fever, poliomyelitis, tetanus, and measles. Today, biotechnology and the use of transgenic animals offer new promise, not dreamed of just a few years ago, for the control of genetic disorders, cancers, and infectious diseases.
With the use of animals come responsibilities for their husbandry, care, and humane treatment. Elaborate safeguards have been implemented by the Animal Welfare Act and the Health Research Extension Act. Those acts give animal care and use committees power to oversee animal use and give investigators and veterinarians new responsibilities in ensuring that animals are not used for trivial purposes and that pain and distress are avoided or minimized. However, some animals used in research to prevent and reduce suffering of humans and animals will be subjected to conditions that cause them pain and distress. There is general agreement on the need to minimize pain and distress, but it has been difficult to bring the necessary melange of information together and to disseminate it throughout the scientific community.
For 40 years the Institute of Laboratory Animal Resources (ILAR) has developed guidelines for the humane use of animals in research, and in 1988 a group was assembled to advise ILAR on whether it should recommend strategies for complying with the new laws. Federal agencies, humane associations, academic institutions, private companies, and national biomedical associations that use or
regulate the use of laboratory animals were consulted about the advisability of this project, and ILAR was encouraged to appoint an expert committee. The Committee on Pain and Distress in Laboratory Animals was thereupon formed and asked to prepare this guide as a method of communicating, to persons with widely differing backgrounds and interests, a deeply held ethical conviction that pain and distress in research animals must be avoided whenever possible and that, when it is not possible to avoid them, every effort must be made to recognize and alleviate them—both for the animals' well-being and to avoid effects of stress on the validity of research data.
The committee was asked to address both pharmacologic and nonpharmacologic methods of prevention and alleviation; to identify techniques or procedures likely to cause pain or distress; to develop a formulary of anesthetics, analgesics, and tranquilizers for laboratory animals; and to discuss known side effects of drugs or techniques that could confound research results. It quickly became clear to the committee that definitions would have to be developed for pain, stress, distress, well-being, and other terms. The committee proposes that stress progresses from acute stress to chronic stress and to distress when the physiologic cost of adapting becomes too high, at which time the animal manifests maladaptive behavior and intervention is indicated. Professional judgment (as used in the text to emphasize that the recommendations of this report should be interpreted in a manner most appropriate for the welfare of animals and the goals of science) is intended to refer to the collective wisdom and experience of the principal investigator, study director, attending veterinarian, and institutional animal care and use committee. Also, and perhaps most important, the committee felt that, to address nonpharmacologic means of prevention and alleviation, especially in regard to non-pain-induced (environmentally induced) stress, it would have to develop criteria and therapeutic strategies quite different from those used for the recognition and treatment of pain.
This volume is intended to increase the awareness and sensitivity of all those working with laboratory animals; provide a ready source of information on appropriate behavioral, biochemical, and physiologic indexes of pain and distress; and present and categorize the methods available for the prevention, reduction, or elimination of pain and distress in various laboratory animal species. The text is organized so as to summarize the scientific basis, recognition, alleviation, and control of pain, stress, and distress in laboratory animals. Chapter 7 discusses the use of euthanasia as a humane strategy of last resort for alleviating pain or distress and presents techniques to reduce stress in animals and in those who must euthanatize them.
General criteria for animal well-being are presented with the understanding that this involves more than good health and the absence of pain and distress and that the refinement of any procedure to improve the well-being of an animal is imperative. The refinement of experimental procedures, husbandry practices, and handling is consistent with the humane goals of Russell and Burch, who proposed
the 3 Rs of replacement, reduction, and refinement to serve as responsible guidelines for the use of animals. This volume focuses on the third R, refinement. We anticipate that this guide will be of interest to researchers, veterinarians, technicians, animal care and use committees, granting agencies, inspectors, site visitors, and others. The committee hopes that it will be useful in the planning or review of experimental procedures and housing and husbandry practices.
Shortcomings of the volume include incompleteness regarding drug side effects and how they can compromise the validity of research results. There is a paucity of information in this regard, but responsibility for it must be left to investigators. Perhaps future revisions of the volume can include more information on side effects and on the pharmacokinetic basis of dosage as additional relevant information becomes available. Readers should note that the report is intended to be a basic guide—it is not encyclopedic. Some readers will want more detailed discussions on some points or the inclusion of more drugs or animal species in the dosage tables. For those readers, an extensive bibliography is provided. The report does not treat the complex topics in cookbook fashion. Rather, it must be interpreted and applied with professional judgment.
The committee extends its appreciation to the contributors, sponsors, and reviewers of this volume; to Jennifer Fujimoto, Office of Campus Veterinary Services, School of Medicine, University of California, San Diego, for contributions to the dosages and references for various species; and to Norman Grossblatt for editing the manuscript. Thomas L. Wolfle and the ILAR staff assisted the committee, and their dedication and contributions made this book possible.
Arthur L. Aronson, Chairman
Committee on Pain and Distress
in Laboratory Animals